Programmed Cell Death 1, or PD-1 (also referred to as PDCD1) related to the present invention is a 50 to 55 kD type I membrane glycoprotein (see Non-Patent Document 1). The expression is recognized in thymocytes when CD4−CD8− cells are differentiated, while it is recognized in an activated CD4−CD8− cells, T-cells, B-cells and monocytes in the peripheral.
PD-1 has an ITIM motif and an ITSM motif in the intracellular domain, which function as inhibitory domains. It is considered that phosphatases, i.e., SHP-1 and SHP-2, mutually interact in the domain to take charge of a suppression function against T-cell receptor complexes.
It has been reported that PD-1 gene is one of genes responsible for autoimmune diseases, such as systemic lupus erythematodes (see Non-Patent Document 2). It has also been indicated that PD-1 serves as a regulatory factor for onset of autoimmune diseases, particularly for peripheral self tolerance, on the ground that PD-1-deficient mice develop lupus autoimmune diseases, such as glomerulonephritis and arthritis (see Non-Patent Documents 3 and Non-Patent Document 4), and dilated cardiomyophathy-like disease (see Non-Patent Document 5).
There are two substances that have been identified as ligands of PD-1: Programmed Death Ligand 1, or PD-L1 (also known as PDCD1L1 or B7-H1) (see Non-Patent Document 6), and Programmed Death Ligand 2, or PD-L2 (also referred to as PDCD1L2 or B7-DC) (see Non-Patent Document 7).
Expression of PD-L1 has been verified not only in immune cells, but also in certain kinds of tumor cell lines (such as monocytic leukemia-derived cell lines, mast cell tumor-derived cell lines, hepatoma-derived cell lines, neuroblastoma-derived cell lines, and various mammary tumor-derived cell lines) and in cancer cells derived from diverse human cancer tissues (see Non-Patent Document 7). Likewise, expression of PD-L2 has been verified in Hodgkin's lymphoma cell lines and others. There is a hypothesis that some of the cancer or tumor cells take advantage from interaction between PD-1 and PD-L1 or PD-L2, for suppressing or intercepting T-cell immune responses to their own (see Non-Patent Document 8).
There are some reports regarding substances inhibiting immunosuppressive activity of PD-1, or interaction between PD-1 and PD-L1 or PD-L2, as well as the uses thereof. A PD-1 inhibitory antibody or a PD-1 inhibitory peptide is reported in Patent Document 1, Patent Document 2, and Patent Document 3. On the other hand, a PD-L1 inhibitory antibody or a PD-L1 inhibitory peptide is reported in Patent Document 4, Patent Document 5, Patent Document 6, and Patent Document 7. A PD-L2 inhibitory antibody or a PD-L2 inhibitory peptide is reported in Patent Document 5 and Patent Document 8.
However, there has been no report regarding a multimer of the present invention, which is formed in the extracellular domains of PD-1, PD-L1 or PD-L2. Further, it has not yet been reported that the multimer is able to be used as a labeling agent of high specificity for detection of cell surface functional molecules such as PD-1.    Patent Document 1: JP 2003-507491    Patent Document 2: WO 2004/004771    Patent Document 3: WO 2004/056875    Patent Document 4: JP No. 2004-533226    Patent Document 5: JP 2005-509421    Patent Document 6: WO 2002/086083    Patent Document 7: WO 2001/039722    Patent Document 8: JP 2004-501631    Non-Patent Document 1: Shinohara T et al, Genomics, 1994, Vol. 23, No. 3, pp. 704-706    Non-Patent Document 2: Prokunina L et al, Nature Genetics, 2002, Vol. 32, No. 4, pp. 666-669    Non-Patent Document 3: Nishimura H et al, International Immunology, 1998, Vol. 10, No. 10, pp. 1563-1572    Non-Patent Document 4: Nishimura H at al, Immunity, 1999, Vol. 11, No. 2, pp. 141-151    Non-Patent Document 5: Nishimura H at al, Science, 2001, Vol. 291, No. 5502, pp-319-332    Non-Patent Document 6: Freeman G J et al, Journal of Experimental Medicine, 2000, Vol. 19, No. 7, pp. 1027-1034    Non-Patent Document 7: Latchman Y at al, Nature Immunology, 2001, Vol. 2, No. 3, pp. 261-267    Non-Patent Document 8: Iwai Y et al, Proceedings of the National Academy of Science of the United States of America, 2002, Vol. 99, No. 19, pp. 12293-12297